1. Field of the Invention
The present invention relates to oligopeptide derivatives for neural protection, regeneration, and repair.
2. Description of the Related Art
Alzheimer's disease (AD) is named after Dr. Alois Alzheimer, a German doctor. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. He found abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles). Today, these plaques and tangles in the brain are considered signs of AD. AD patients may have symptoms such as forgetfulness, slovenliness, anxiety, aggressiveness, or cognitive impairment. Eventually, patients suffer from AD need complete care from friends, relatives, or care-givers. The symptoms of AD in the early stage may be confused with age-related physiological and psychological changes and accurate laboratory diagnostic method for AD is still unavailable, making diagnoses and control of AD difficult. Pathological changes of AD include, not only senile plaques with β-amyloid deposits and neurofibrillary tangles in the cerebral cortex, but also loss of cholinergic neurons in the basal forebrain and decrease of acetylcholine and choline acetyltransferase in the cerebral cortex.
Recent studies show that nerve growth factors (NGF) and brain-derived neurotrophic factor (BDNF) apparently enhance the growth and differentiation of embryonic cholinergic neurons in vitro. The application of NGF or BDNF to the lateral ventricle or brain parenchyma can protect cholinergic neurons of basal forebrain from degeneration caused by dissection of hippocampus and thus alleviate the severity of dementia. Besides nerve growth factors and brain-derived neurotrophic factor, known neurotrophic factors also include glial cell-derived neurotrophic factor (GDNF), neurotrophin 3 (NT-3), vasoactive intestinal peptide (VIP), NAP, activity-dependent neurotrophic factors (ADNFs), and activity-dependent neurotrophic protein (ADNP).
ADNP and ADNFs were first isolated from glial cells by Dr. Brenneman (National Institute of Health) in collaboration with Dr. Gozes (Tel Aviv University) during the study of VIP. ADNP and ADNFs both are ultra potent neurotrophic factors with activities around femtomolar level. ADNF-14 (VLGGGSALLRSIPA) (SEQ ID NO: 1) derived therefrom has stronger activity than ADNP. Follow-up studies of Brenneman and Gozes reveal that ADNF-9. (SALLRSIPA) (SEQ ID NO: 2) and NAP (NAPVSIPQ) (SEQ ID NO: 3) both derived from ADNF are also femtomolar-acting neurotrophic factors.
In vitro experiments found that ADNF-14, ANDF-9 and NAP can protect neural cells from degeneration or death caused by GP120 of HIV, NMDA (an excitatory toxin), dopamine, 6-hydroxydopamine, ferrous sulfate, hydrogen peroxide, β-amyloid (an inferential neuron toxin of Alzheimer's disease), tetrodotoxin (a sodium channel blocker), and presenilin-1. In in vivo experiments, ADNF-14, ADNF-9 and NAP also showed neuroprotective activities in cerebral palsy mouse and apolipoprotein E knock-out mouse and prevented choline-deficient mouse from loss of the abilities of spatial learning and memorization. In addition, a long term protection (about 5 days) may be achieved by a short term (2 hours) exposure to these peptides. The various neuroprotective and neurotrophic effects of these peptides indicate that they may act at the very basic steps of molecular biology for cells to survive.
The discovery of ADNF-14, ADNF-9 and NAP established a new concept of designing femtomolar-active and long-acting oligopeptides derived from high molecular weight proteins. These peptides can be leads for the development of drugs to alleviate, postpone, or prevent the onset of Alzheimer's disease and also for the treatment of Parkinson's disease, cerebral vascular disease, or the regeneration of neurons.
Though ADNF-14, ADNF-9, and NAP are potential candidates for drug development, they also have the same drawbacks as common peptide drugs. For example, peptides may be degraded by proteases and lose their activities; the configuration thereof with a higher degree of freedom might lower their affinities and selectivity toward receptors, hinder the drugs to penetrate cell membrane or blood brain barrier, and exhibit multiple mechanisms of action that make the concentration-activity relationships thereof do not follow a simple sigmoid curve. One purpose of this invention is overcoming the described drawbacks to provide a novel neurotrophic drug with excellent stability, good absorption, long half-life, and superior drug exposure for the treatment of Alzheimer's disease, Parkinson's disease, stroke, or cognitive impairment resulting from neural intoxication, neural injury, spinal injury, or coronary artery bypass surgery.